The overall aim of this project is to identify the cellular receptor(s) for the feline lentiviruses and to examine the role of the virus-receptor interaction in the pathogenesis of AIDS. The project will build upon our earlier work demonstrating that CXCR-4 is the major, if not sole, co-receptor for the feline immunodeficiency virus (FIV) lentivirus of the domestic cat. In the domestic cat, FIV infection induces an immunodeficiency syndrome similar to AIDS in HIV- infected humans. In the proposed studies, we will ask whether receptor usage determines pathogencity of feline lentiviruses in domestic vs. non-domestic cats as is postulated for receptor usage and pathogenicity in primate lentiviral systems. Several lines of evidence suggest that primary strains of FIV require the co-expression of another cell surface molecule (perhaps analogous to the HIV receptor CD4) in addition to CXCR-4 in order to infect all target cells. Aim 1 will determine whether FIV utilizes a primary receptor beside CXCR-4 for infection of feline cells. We will use retroviral pseudotypes to screen cDNA libraries for additional receptor(s) and/or co- receptors and the function of the molecule(s) will be characterised. Aim 2 will examine the link between receptor-usage and pathogenicity. We will ask whether receptor usage varies among feline lentivirus isolates, i.e.: (a) isolates characterized as pathogenic vs. non-pathogenic in experimental studies; (b) isolates obtained from asymptomatic vs. symptomatic naturally infected cats; and (c) isolates transmitted via different routes in experimental studies. Aim 3 will investigate whether non-domestic vs. domestic cat lentiviruses use different vs. common viral receptors. The lentiviruses of the non-domestic cats appear to be more ancient and more adapted to their host species than is FIV to the domestic cat. We will investigate whether receptor-usage is a determinant of host-adaptation. These studies will elucidate the cellular receptor(s) for the feline lentiviruses, determine whether changes in receptor usage relate to pathogenicity, and forecast the future of both FIV/domestic cat and HIV/human receptor-virus evolutionary outcomes.